1-[(1,1-diphenyl)-1-alkenyl]piperazine derivatives, method of preparation and pharmaceutical compositions in which they are present

ABSTRACT

The invention relates to 1-[(1,1-diphenyl)-1-alkenyl]piperazine derivatives corresponding to general formula I: ##STR1## in which R 1 , R 2 , R 3 , R 4  and R 5 , which are identical or different, represent a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkenyl group, a lower alkoxy group or the trifluoromethyl group; n is an integer between 1 and 3; m is an integer from 0 to 3; Z represents a hydrogen atom, a lower alkyl group or an aryl group of the formula: ##STR2## in which R 6  has the same meaning as R 1 , R 2 , R 3  or R 4  ; and A is an oxygen atom or a group ##STR3## and to their pharmaceutically acceptable salts. Application: pharmeutical compositions with antidepressant properties.

The present invention relates to 1-[(1,1-diphenyl)-1-alkenyl]piperazine derivatives. It also relates to the pharmaceutically acceptable salts of these derivatives. A further subject of the present invention is the methods for their preparation and the pharmaceutical compositions in which they are present.

The derivatives according to the invention have valuable pharmacological properties on the central nervous system, in particular antidepressant properties, but possess little or no sedative activity.

The derivatives of the invention correspond to the following general formula: ##STR4## in which:

R₁, R₂, R₃, R₄ and R₅, which are identical or different, represent a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkenyl group, a lower alkoxy group or the trifluoromethyl group;

n is an integer between 1 and 3;

m is an integer from 0 and 3;

Z represents a hydrogen atom, a lower alkyl group or an aryl group of the formula: ##STR5## in which

R₆ has the same meaning as R₁, R₂, R₃ or R₄ ; and

A is an oxygen atom or a group ##STR6##

In the present description:

"lower alkyl" denotes linear or branched, saturated aliphatic hydrocarbon radicals containing 1 to 6 carbon atoms; the preferred alkyl group for the purposes of the invention is the methyl group;

"lower alkenyl" denotes linear or branched, unsaturated aliphatic hydrocarbon radicals containing 1 to 6 carbon atoms; and

"lower alkoxy" denotes a hydroxyl group substituted by a lower alkyl as defined above.

The compounds of the invention can be obtained by reacting a derivative of general formula II: ##STR7## in which Z, m and A are as defined above and X is a tosyl group or a halogen atom (for example bromine or chlorine), with a substituted piperazine of general formula III: ##STR8## in which R₁, R₂, R₃, R₄ and n are as defined above, in the presence of sodium or potassium iodide and one equivalent of sodium or potassium carbonate.

This reaction is carried out by heating in an appropriate solvent such as an aromatic hydrocarbon, for example toluene or benzene, or in another solvent such as methyl ethyl ketone.

The derivatives of general formula III can easily be obtained by reacting a derivative of general formula IV: ##STR9## in which R₁, R₂, R₃, R₄ and n are as defined above and Y is a bromine or chlorine atom, with anhydrous piperazine of formula V: ##STR10##

In general, 4 equivalents of the compound of formula V are used per equivalents of the compound of formula IV.

This condensation reaction is carried out by refluxing in an appropriate solvent such as an aromatic hydrocarbon, for example benzene or toluene.

The compounds of formula IV can be prepared by the method described by DAVIS et al. in J. Med. Chem. 10, (4) 627-635, 1967.

The compounds of formula II in which m is an integer equal to 2, A is an oxygen atom, Z is an aryl radical, X is a chlorine atom and R₁, R₂, R₃, R₄ and R₅ are as defined above can also be obtained by the method described by SLIWA et al. in "Bull. Soc. Chim. Fra., 1972, 4, 1540-1544", according to the following reaction scheme: ##STR11##

The other compounds of formula II in which A is oxygen can be obtained by conventional methods involving the addition of phenates onto dihalogenoalkyl compounds. Some of these compounds are available commercially.

The compounds of formula II in which A is the group ##STR12## can be obtained by the well-known Friedel-Crafts reaction. In the examples which follow, commercially available parafluorobutyrophenone chloride was used.

The acid addition salts of the derivatives of formula I according to the invention can be obtained by conventional methods with acids commonly used for the preparation of pharmaceutically acceptable salts, such as hydrochloric acid, methanesulfonic acid, tartaric acid, maleic acid or fumaric acid.

As stated above, the derivatives according to the invention possess valuable pharmacological properties on the central nervous system and especially antidepressant properties.

Therefore the invention also relates to the pharmaceutical compositions in which a derivative according to the invention is present as the active principle, in combination with a pharmaceutically acceptable vehicle.

The compositions according to the invention can be administered orally or by injection. They can take the form of solutions, tablets, gelatin capsules, pills or injectable compositions.

The invention will now be described in greater detail by means of the illustrative examples which follow. In these examples, the derivatives prepared were identified and characterized by studying their NMR and infrared spectra and also by their elemental analyses.

The piperazine derivative used as the starting compound was prepared by the following procedure: Preparation of 1-[(1,1-diphenyl)-1-buten-4-yl]piperazine

A solution of 34.4 g of anhydrous piperazine in 110 ml of toluene was placed in a 250 ml reactor. The mixture was heated to the reflux temperature and a solution of 28.7 g of 4-bromo-1,1-diphenyl-1-butene in 15 ml of toluene was added dropwise. The mixture was stirred for 1 h.

The solution was cooled. After filtration, it was taken up with 100 ml of water and decanted. The toluene phase was extracted with 3 times 50 ml of a 7% solution of acetic acid. The extract was neutralized with sodium carbonate in the presence of 100 ml of CH₂ Cl₂. The organic phase was decanted and dried and the solvent was evaporated off. 22.5 g of a brown oil were collected; this was used in the crude state in the next example. Empirical formula: C₂₀ H₂₄ N₂ O.

NMR spectrum (solvent CDCl₃, reference TMS):

1.2 ppm (s), 1H, NH; 2.2 ppm (m), 8H, CH₂ --N--CH₂ --CH₂ --C═C; 2.7 ppm (m), 4H, H-N-CH₂ ; 5.8 ppm (t), 1H, C═CH; 7.0 ppm (M), 10H, φ.

EXAMPLE 1 Preparation of 1-[(1,1-diphenyl)-1-buten-4-yl ]-4-[1-(2-(4-fluorophenoxy)ethyl]piperazine dimethanesulfonate (1)

A solution of 13.33 g of 1-(1,1-diphenyl-1-buten-4-yl)piperazine, obtained in Example 1, in 150 ml of methyl ethyl ketone, 10 g of 2-bromo-1-(4-fluorophenoxy)ethane, 9.45 g of Na₂ CO₃ and 0.1 g of anhydrous NaI were placed in a 250 ml reactor.

The reaction mixture was refluxed for 18 h and then cooled. After filtration, the solution was washed twice with 80 ml of water.

It was decanted and dried and the solvent was evaporated off. 10.5 g of a yellow oil were collected.

To purify the product, the hydrochloride was prepared and recrystallized from acetone.

100 ml of a 1N solution of hydrochloric acid were added to 7 g of the crude oil obtained above. The mixture was stirred for 30 min. After filtration and rinsing twice with 50 ml of water, the hydrochloride obtained was crystallized from 30 ml of acetone.

The base was freed with Na₂ CO₃ in the presence of 50 ml of water and 50 ml of CH₂ Cl₂. The organic phase was decanted and dried and the solvent was evaporated off to give 6.3 g of an oil.

The dimethanesulfonate was prepared by reacting a solution of 4 g of the resulting product in ether with 1.8 g of methanesulfonic acid to give a solid with a melting point of 150° C. and the empirical formula: C₂₈ H₃₁ FN₂ 0.2(CH₄ O₃ S).

NMR spectrum of the base (solvent CDCl₃, reference TMS):

2.5 ppm (M), 14H, ═C--CH₂ --CH₂ --N--CH₂ --CH₂ ; 4.0 ppm (t),

2H, O--CH₂ ; 6.0 ppm (t), 1H, C═CH; 7.0 ppm (m), 14H, φ.

IR spectrum (1% in KBr):

2500 cm⁻¹ (N⁺ -H); 1200 cm⁻¹ (SO₂); 1060 cm⁻¹ (SO₂).

EXAMPLES 2 to 17

Compounds no. 2 to 17 indicated in the table below were obtained by following the procedure described in Example 1 above.

                                      TABLE I                                      __________________________________________________________________________      ##STR13##                                                                                                             Melting                                                                              Molecular                        Compound                                                                             R.sub.1 = R.sub.2 = R.sub.3 = R.sub.4                                                      R.sub.5                                                                              Z     n  m  A   point °C.                                                                     weight Salt                      __________________________________________________________________________     1     H           4-F   H     2  1  O   150   622    Dimethanesulfonate        2     H           2-CH.sub.3                                                                           H     2  1  O    100.sup.a                                                                           618                              3     H           3-Cl  H     2  1  O    90.sup.a                                                                            638.5                            4     H           2-CH.sub.3                                                                            ##STR14##                                                                           2  2  O    80.sup.a                                                                            708                              5     H           4-F   "     2  2  O    85.sup.a                                                                            712                              6     H           4-F   H     2  2  O   155   636                              7     H           4-F   H     2  2  C═O                                                                            140   648                              8     H           4-F   H     2  3  O   134   650                              9     H           H     H     2  1  O   200   604                              10    H           4-t(C.sub.4 H.sub.9)                                                                 H     2  2  O   222   674                              11    H           4-Cl  H     2  2  O   156   625.5                            12    H           3-OCH.sub.3                                                                          H     2  2  O   189   648                              13    H           4-F   H     2  3  O   154   650                              14    H           4-CH.sub.3                                                                           H     2  3  O   157   646                              15    H           4-t(C.sub.4 H.sub.9)                                                                 H     2  3  O   191   688                              16    H           4-F   H     3  1  O   165   636                              17    R.sub.1 = 4-F,                                                                             4-F   H     2  1  O   151   640                                    R.sub.2 = R.sub.3 = R.sub.4 = H                                          __________________________________________________________________________      .sup.a decomposition point                                               

The NMR spectra of these compounds are given below (solvent CDCl₃ --internal reference TMS):

Derivative 2: 2.3 ppm (s), 3H, CH₃ ; 2.5 ppm (m), 14H, CH₂ --CH₂ --N--CH₂ --CH₂ --N; 4.1 ppm (t), 2H, O--CH₂ ; 6.1 ppm (t), 1H, C═CH; 7.0 ppm (m), 14H, φ.

Derivative 3: 2.5 ppm (m), 14H, CH₂ --CH₂ --N--CH₂ --CH₂ --N: 4.0 ppm (t), 2H, O--CH₂ ; 6.0 ppm (t). 1H, C═CH; 7.0 ppm (m), 14H, φ.

Derivative 4: 2.3 ppm (m), 16H, CH₂ --CH₂ --N--CH₂ --CH₂ --N--CH₂ ; 2.4 ppm (s), 3H, CH₃ ; 5.1 ppm (t), 1H, CH--O; 5.9 ppm (t), 1H, C═CH; 7.1 ppm (m), 19H, φ.

Derivative 5: 2.4 ppm (m), 16H, CH₂ --CH₂ --N--CH₂ --CH₂ --N--CH₂ ; 5.1 ppm (t), 1H, O--CH; 6.0 ppm (t), 1H, C═CH; 7.0 ppm (m), 19H, φ.

Derivative 6: 2.0 ppm (m), 2H, C--CH₂ --C--O; 2.3 ppm (m), 14H, CH₂ --CH₂ --N; 3.7 ppm (t), 2H, O--CH₂ ; 5.8 ppm (t), -H, C═CH; 6.5 to 7.2 ppm (m), 14H, φ.

Derivative 7: 1.6 to 2.6 ppm (m), 16H, CH₂ --CH₂ --N; 1.8 ppm (t), 2H, CH₂ --C═O; 5.8 ppm (t), 2H, C═CH; 6.5 to 7.8 ppm (m), 14H, φ.

Derivative 8: 1.8 ppm (m), 4H, N--C--CH₂ --CH₂ --C--O; 2.3 ppm (m), 12H, CH₂ --N; 3.7 ppm (t), 2H, O--CH₂ ; 5.8 ppm (t), 1H, C═CH; 6.5 to 7.4 ppm (m), 14H, φ.

Derivative 9: 2.4 ppm (m), 14H, CH₂ --CH₂ --N--CH₂ --CH₂ --N--CH₂ ; 4.0 ppm (t), 2H, CH₂ O; 6.0 ppm (t), 1H, C═CH; 7.2 ppm (m), 15H, φ.

Derivative 10: 1.2 ppm (s), 9H, CH₃ ; 1.9 ppm (m), 2H, C--CH₂ --C; 2.3 ppm (m), 14H, CH₂ --N; 4.0 ppm (t), 2H; CH₂ O; 6.0 ppm (t), 1H, C═CH; 1.0 ppm (m), 14H, φ.

Derivative 11: 1.8 ppm (m), 2H, CH₂ ; 2.4 ppm (m), 14H, CH₂ N; 3.9 ppm (t), 2H, CH₂ O; 6.0 ppm (t), 1H, C═CH; 7.0 ppm (m), 14H, φ.

Derivative 12: 2.3 ppm (m), 16H, CH₂ --N, CH₂ ; 3.5 ppm (s), 3H, CH₃ O; 3.7 ppm (t), 2H, CH₂ O; 5.9 ppm (t), 1H, C═CH; 6.7 to 7.4 ppm (m), 14H, φ.

Derivative 13: 1.7 to 2.4 ppm (m), 18H, CH₂ --N, CH₂ ; 3.8 ppm (t), CH₂ O; 6.0 ppm (t), 1H, C═CH; 6.8 to 7.2 ppm (m), 14H, φ.

Derivative 14: 1.8 ppm (m), 4H, N--C--CH₂ --CH₂ --C--O; 2.4 ppm (s), 3H, CH₃ ; 2.3 to 2.6 ppm (m), 14H, CH₂ --CH₂ --N--CH₂ --CH₂ --N--CH₂ ; 3.9 ppm (t), 2H, CH₂ --O; 6.0 ppm (t), 1H, CH═C; 6.5 to 7.2 ppm (m), 14H, φ.

Derivative 15: 1.2 ppm (s), 9H, CH₃ ; 1.7 ppm (m), 4H, N--C--CH₂ --CH₂ --C--O; 2.1 to 2.6 ppm (m), 14H, CH₂ --CH₂ --N--CH₂ --CH₂ --N--CH.sub. ; 3.8 ppm (t), 2H, CH₂ --O; 6.0 ppm (t), 1H, CH═C; 6.3 to 7.3 ppm (m), 14H, φ.

Derivative 16: 1.6 to 3.3 ppm (m), 16H, CH₂ --CH₂ --CH₂ --N--CH₂ --CH₂ --N--CH₂ --C--O; 4.0 ppm (t), 2H, CH₂ --O; 6.0 ppm (t), 1H, CH═C; 6.7 to 7.4 ppm (m), 14H, φ.

Derivative 17: 2.2 to 2.7 ppm (m), 4H, CH₂ --N, CH₂ --C═C; 4.0 ppm (t), 2H, CH₂ --O; 6.0 ppm (t), 1H, CH═C; 6.8 to 7.4 ppm (m), 13H, φ.

I - TOXICITY TEST

The toxicity of the compounds of the invention was determined by the following test:

Determination of the 50% lethal dose (LD₅₀) in mice

The test product was administered intraperitoneally to groups of 5 male mice and 5 female mice at a rate of 0.1 ml per 10 g of body weight.

The following doses were used:

100--150--200--300--400 mg.kg⁻¹ IP

The LD₅₀ determined from the mortality observed is indicated in the following table, together with that of the known antidepressants AMINEPTINE and IMIPRAMINE.

                  TABLE II                                                         ______________________________________                                                            FIDUCIAL LIMITS                                                                CALCULATION ACCORDING                                                 LD.sub.50 IP                                                                            TO LITCHFIELD and                                           No.       mg/kg    WILCOXON                                                    ______________________________________                                         1         231      195-274                                                     2         #200     --                                                          3         #250     --                                                          4         386      279-453                                                     5         314      234-421                                                     6         247      206-296                                                     7         #175     --                                                          8         199      172-229                                                     AMINEPTINE                                                                               #200     --                                                          IMIPRAMINE                                                                               #115     --                                                          ______________________________________                                    

II - PHARMACOLOGICAL TESTS

The pharmacological properties of the compounds of the invention were determined using the following tests:

Experimental protocols

1. Study of the spontaneous motility

The motor activity of mice was determined using a Boissier and Simon photoelectric actimeter.

The mice are placed in groups of five in a box closed with a lid, through which two perpendicular rays of light pass; the mice cut across these rays as they move.

These movements are counted by a meter, which is read 30 min and 1 h after the administration of the test derivative.

2. Exploratory behavior

30 min after the intraperitoneal administration of the derivatives according to the invention, each mouse is placed on an automated hole-board for 5 min and the number of holes explored is noted every minute.

A 50% effective dose can be calculated from the results obtained.

3. Muscle-relaxing action (traction test)

This test assesses the presence or absence of redressments in a mouse brought up to a horizontal wire with its front paws.

The number of mice which are unable to grip the wire with one of their back paws within 5 s is noted.

A 50% effective dose can be calculated from the results obtained.

4. Rectal temperature

The rectal temperature of mice is measured using an Ellab. ctd 85 electric thermometer.

A first reading is taken immediately before the injection of the test derivative.

The temperature is noted 30 min and 1, 2, 3 and 4 h after the injection.

5. Peripheral analgesic activity

A peritoneal pain is caused in mice by the intraperitoneal injection of phenylbenzoquinone (PBQ).

The test assesses the decrease in the pain syndrome, characterized by an abdominal twisting movement, which is caused by injecting the test derivative 30 min before the administration of PBQ.

The 50% effective dose is calculated from the percentage decrease in the pain syndrome relative to the control animals.

6. Central analgesic activity

This test assesses an increase in the time which is spent on a plate, heated to 60° C., by mice treated with the test derivative 30 min before the start of the test.

The 50% effective dose is calculated from the percentage increase in the time spent on the hotplate (licking of the paws or, in some cases, jumping).

7. Interaction with pentobarbital

This test assesses any increase in the sleep induced by barbiturate which is caused by administering the test derivative intraperitoneally 5 min before the intraperitoneal injection of pentobarbital (37.5 mg/kg).

A 50% effective dose can be calculated from the results obtained.

8. Interaction with oxotremorine

As oxotremorine is an agonist of cholinergic receptors, substances which antagonize the trembling, hypothermia and peripheral signs (salivation, piloerection) induced by this product can be considered to be anticholinergics.

The test derivative is administered 30 min before the intraperitoneal injection of oxotremorine.

9. Yohimbine test

The test derivative is administered 30 min before the injection of yohimbine (25 mg/kg IP).

The number of deaths is counted 24 h after the injection of yohimbine.

10. Apomorphine test

The test derivative is administered intraperitoneally 30 min before the injection of apomorphine. Apomorphine is injected subcutaneously at a rate of 16 mg/kg.

The mice are then isolated in small cages.

The redressments, stereotypies and rectal temperature of the animals are noted.

11. Reserpine test

The test derivative is administered intraperitoneally.

The mice are placed in individual cages.

Reserpine (2.5 mg/kg) is injected intraperitoneally 30 min after the injection of the test derivative.

The occlusion of the eyelids is noted every 30 min and the rectal temperature is taken 2 h, 3 h and 4 h after the injection of reserpine.

12. Anticataleptic test with prochloroperazine

(PCPZ)

The test derivative is injected and each rat is placed in an individual cage.

25 mg/kg of PCPZ are injected 30 min later.

Every 30 min, each rat is placed on a sheet of filter paper and its front paws are crossed with the back paws on the same side.

13. Porsolt's test

The test derivative is administered intraperitoneally 60 min before the start of the test.

The mice are then placed in a beaker half-filled with water for 6 min.

The time which the animals spend moving in the water is calculated.

14. Tail suspension test (TST)

A rodent placed in a disagreeable situation with no obvious means of escape (hanging by its tail) rapidly tends to reduce its evasive motor activity.

The apparatus comprises two suspending units, a central unit and a microcomputer which integrates the operator's commands and the statistical calculations.

The test derivative is administered intraperitoneally 30 min before the mice are suspended.

The various parameters (immobility time, total energy, power of the movements) are measured automatically for 6 min.

Results

The results obtained are collated in Table III below. These results show that the derivatives of the invention are active on the central nervous system and have antidepressant properties in particular.

Comparative tests

By way of comparison, the above tests were carried out with AMINEPTINE, IMIPRAMINE and MIANSERINE, which are products known for their antidepressant properties. The results obtained are also included in Table III below. These results show that the derivatives of the invention, and especially compound no. 1, are antidepressants with a greater activity than the known antidepressants.

The compound of Example 1 was furthermore tested for its antiserotoninergic activity according to the following tests:

Experimental protocols

1. Head twitches caused by 5-hydroxytryptophane (5-HTP)

Animals: male mice of 25±1 g

At time T-3 h, 100 mg/kg of pargyline were injected intraperitoneally.

At time T-30 minutes, the test product or distilled water (control) was injected intraperitoneally.

At time T═O, 5-HTP was injected intraperitoneally at a dose of 4 mg/kg.

All the jerky head movements made by the mice were observed over a 1-minute period every twelve minutes.

The mean number of movements was calculated and compared with the control group.

2. Head twitches caused by 5-methoxydimethyltryptamine (5-MeODMT)

Animals: male mice of 25±1 g

At time T-3 hours, 100 mg/kg of pargyline were injected intraperitoneally.

At time T-30 minutes, the test product or distilled water (control) was injected intraperitoneally.

At time T═O, 5-MeODMT was injected intraperitoneally at a dose of 4 mg/kg.

The number of head twitches was observed.

The mean number of movements was calculated and compared with the control group.

3. Penile erections caused by apomorphine

The test product was administered parenterally or orally to rats, placed in a transparent cage, 30 minutes before the intraperitoneal injection of 0.20 mg/kg of apomorphine.

The number of penile erections was recorded over the 30 minutes following the injection of apomorphine.

A statistical study was carried out by comparison with the numbers of erections in the control rats.

4. Tryptamine test

Tryptamine causes characteristic convulsive seizures in rats.

The test product was administered intraperitoneally 1 hour before the intravenous injection of tryptamine (40 mg/kg).

The ability of the product to reduce the intensity and/or duration of the convulsive seizure was observed.

Statistical calculations were made by comparison with the results observed in the control animals.

5. Grahame Smith's test

Animals: male rats of 200±10 g

At time T-30 minutes, the test product was administered intraperitoneally.

At time T═O, an MAOI was administered intraperitoneally (tranylcypromine, 20 mg/kg).

At time T+20 minutes, 250 mg/kg of tryptophan were administered (IP).

The temperature of the rats was recorded every 30 minutes for 200 minutes and the various clinical signs (motor agitation--hypersalivation--catatonia of the tail--hyperesthesia--thrashing of the tail, etc.) were noted on a scale of 0 to 1.

The mean temperatures and the average symptoms observed were calculated by comparison with the controls.

Results

The results obtained are collated in Table IV below. These results show that the compound of Example 1 possesses an antiserotoninergic activity.

    TABLE III                 Antagonism        Muscle-       of the Antagonism Inter-      relaxing  Peripheral   Inter-  symptoms of the action    action      analgesic Central Narcosis action Yohimbine induced by symptoms with      Porsolt's   Exploratory Traction Rectal activity analgesic induced with      toxicity APOMORPHINE induced by PCPZ test TST  Activity behavior test      tempera- mouse activity by bar- oxo- mouse 16 mg · kg.sup.-1      RESERPINE rat mouse mouse  mouse mouse mouse ture ED.sub.50 mg ·       mouse mg · biturate tremorine ED.sub.50 SC mouse mouse mg      · kg.sup.-1 mg · kg.sup.-1 mg · kg.sup.-1  mg      · kg.sup.-1 IP mg · kg.sup.-1 IP mg ·      kg.sup.-1 IP mouse kg.sup.-1 IP kg.sup.-1 IP mouse mouse mg ·      kg.sup.-1 IP mg ·  kg.sup.-1 IP mg · kg.sup.-1 IP IP      IP IP        1 No modi- No modi- No modi- Tran- 1.50 No No in- No 31 Antagonizes      Antagonizes Anta- Active Active  fication fication fication sient      activity crease antago-  the hypo- the hypo- gonizes up to up to  up to      up to up to hypo-  up to in the nism  thermia at thermia at the 3.12      3.12  25 25 25 thermia  12.5 sleep   6.25 3.12 cata-        induced      lepsy        by bar-     at 25        biturate 2 -- No modi- -- No modi-      -- No -- No Increase No Practically -- Active Active   fication      fication  activity  antago- above antagonism zero  at 25 at 25   up to         nism 6.25  antagonism   25 3 -- No modi- -- No modi- -- No Increase      No Substan- No Very slight -- Active Active   fication  fication      activity in the antago- tial antagonism antagonism at 12.5 at 25   up to          sleep nism increase   25     induced  at 12.5        by bar-      biturate        at 25.0 4 Increase No modi- -- No modi- 1.50 No No in-      No Slight No Antagonizes Anta- In- In-   fication  fication  activity      crease antago- increase antagonism the hypo- gonizes active active   up      to      nism   thermia at the   25         12.5 cata-             lepsy                 at 12.5             and 25 5 No modi- No modi- No modi- No      modi- -- No Increase No No No Antagonizes -- In- In-  fication fication      fication fication  activity in the antogo- increase antagonism the hypo-       active active  up to 25 up to 25 up to 25    sleep nism   thermia at          induced    12.5        by bar-        biturate        at 25      mg ·        kg.sup.-1 6 Distinct No modi- No modi- -- Slight No      Slight No 25 No Antagonizes No an- In- In-  decrease fication fication      activity activity increase antago-  antagonism the hypo- tagonism active      active   up to 25 up to 25   up to 25 in the nism   thermia at at 25         sleep    12.5        induced        by bar-        biturate 7      ED.sub.50 7.5 No modi- No modi- Hypo- 0 -- Increase No >25 No No No an-      In- --  mg · kg.sup.-1 fication fication thermia   in the      antago-  antagonism antagonismtagonism active   up to 25 up to 25 at 25       sleep in- nism        duced by        barbitur-        ate 8 Decrease      No modi- No modi- Trans- 6.25 -- Slight No >25 No Antagonizes Anta- In-      --  at 25 fication fication ient   increase antago-  antagonism the      hypo- gonizes active   up to 25 up to 25 hypo-   in the nism   thermia      at the     thermia   sleep    12.5 cata-        induced     lepsy      by bar-     at 25        biturate 14 Decrease No modi- No modi- No 2.5      Signifi- Increase No >25 Antagonizes Antagonizes Practi- Active Active      fication fication modi-  cant at in the anta-  the hypo- the hypo- cally      at at     fication  25 sleep gonism  thermia thermia in- 25.0 25.0       induced     active        by bar-        biturate        at 4.9 16      Substan- No modi- No modi- No 4.5 No No Anta- Little No No In- In-      Increase  tial fication fication modi-  activity increase gonizes      activity antagonism antagonism active acitive in the  increase      fication    the      energy         hypo-      and         thermia      power               of the               move-               ments 17      Increase No modi- Active No 5.2 No No No >25 Antagonizes Antagonizes      Slight Active Very  at 7.9 fication at 25 modi-  activity increase      antagonism  the hypo- the hypo- anta- at active     fication      thermia at thermia at gonism 6.25 at           6.25 a low dose      1.58               Antagonism              of the Antagonism    Muscle      Peripheral    symptoms of the Inter-    relaxing  analgesic Central      Inter-  induced by symptoms action Porsolt's   Exploratory action Rectal      activity analgesic action Yohimbine APOMORPHINE induced by with test TST       Activity behavior Traction temper- mouse ED.sub.50 activity with oxo-      toxicity 16 mg · kg.sup.-1 RESERPINE PCPZ rat mouse mouse PRO-      mouse mouse test mouse ture mg · kg.sup.-1 mouse tremorine      mouse ED.sub.50 SC mouse mouse mg · kg.sup.-1 mg ·      kg.sup.-1 mg · kg.sup.-1 DUCT mg · kg.sup.-1 IP mg      · kg.sup.-1 IP mg ·       kg.sup.-1 IP mouse IP mg · kg.sup.-1 IP mouse mg ·      kg.sup.-1 IP mg · kg.sup.-1 IP mg · kg.sup.-1 IP IP IP      IP        AMI- Increases No modi- No action Trans- -- -- No Increase No Antagoniz      es -- Active Active NEP- the fication  ient   antagonism above 10      antagonism the hypo-  at 6.25 at 12.5 TINE activity   hypo-      thermia          thermia IMI- Increases No modi- No action Trans- -- -- Decreases      Increase Antagonizes Antagonizes Anta- Active Active PRA- the fication      ient   the above 15 the hypo- the hypo- gonizes at 8 at 8 MINE activity       hypo-   trembling  thermia thermia at 15  at 15   thermia MI- -- -- --      -- -- -- -- -- -- -- -- Active Active AN            at at SE-      16 3.13 RINE

                                      TABLE IV                                     __________________________________________________________________________     ANTISEROTONINERGIC ACTIVITY                                                           Antagonism of the head                                                                      Antagonism of the                                                 twitches induced by                                                                         penile erections                                                                         Tryptamine test                                                                        Grahame Smith's test                            5-HTP 5-MeODMT                                                                              and yawning (rats)                                                                       (rats)  (rats)                                   __________________________________________________________________________     Compound 1                                                                            ↓ as from                                                                     ↓ as from                                                                      antagonism as from                                                                       active as from                                                                         ↓ hyperthermia and                (IP)   18.8 mg/kg                                                                           6.25 mg/kg                                                                            6.25 mg/kg                                                                               50 mg/kg                                                                               clinical signs                           Compound 1                                                                            nt    nt     nt        nt      ↓ at 37.5 mg/kg                   (PO)                                                                           Mianserin                                                                             nt    nt     nt        active at 6.0                                    (IP)                          mg/kg                                            __________________________________________________________________________      nt = not tested                                                           

We claim:
 1. 1-[(1,1-Diphenyl)-1-alkenyl]piperazine derivatives corresponding to formula I: ##STR15## in which: R₁, R₂, R₃, R₄ and R₅, which are identical or different, represent a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkenyl group, a lower alkoxy group or the trifluoromethyl group;n is an integer from 1 to 3; m is an integer from 0 to 3; Z represents a hydrogen atom, a lower alkyl group or an aryl group of the formula: ##STR16## in which R₆ has the same meaning as R₁, R₂, R₃ or R₄ ; and A is an oxygen atom or a group ##STR17## and their pharmaceutically acceptable salts.
 2. Derivative according to claim 1, which is 1-[(1,1-diphenyl)-1-buten-4-yl]-4-[1-(2-(4-fluorophenoxy) ethyl]-piperazine.
 3. A method for the preparation of the derivatives as claimed in claim 1, which consists in reacting a derivative of general formula II: ##STR18## in which Z, m and A are as defined above and X is a tosyl group or a halogen atom (for example bromine or chlorine), with a piperazine of general formula III: ##STR19## in which R₁, R₂, R₃, R₄ and n are as defined above; in the presence of sodium or potassium iodide and one equivalent of sodium or potassium carbonate, and in converting the resulting compounds to their pharmaceutically acceptable salts.
 4. A pharmaceutical composition for use in treating depressant in which an antidepressant effective amount of a derivative as claimed in claim 1 is present as the active ingredient, in combination with a pharmaceutically acceptable vehicle.
 5. A method for treating depressant which comprises administrating an antidepressant effective amount of a piperazine derivative corresponding to formula I: ##STR20## in which: R₁, R₂, R₃, R₄ and R₅, which are identical or different represent a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkenyl group, a lower alkoxy group or the trifluoromethyl group;n is an integer from 1 to 3; m is an integer from 0 to 3; Z represents a hydrogen atom, a lower alkyl group or an aryl group of the formula: ##STR21## in which R₆ has the same meaning as R₁, R₂, R₃ or R₄ ; and A is an oxygen atom or a group ##STR22## and their pharmaceutically acceptable salts for the manufacture of drugs active on the central nervous system. 